Field of the Invention
The present invention relates to stable aerosol solution compositions, comprising glycopyrronium bromide and formoterol, or a salt thereof or a solvate of said salt, optionally in combination with an inhalation corticosteroid (ICS), stabilized by a mineral acid, which are contained in an aerosol can. The present invention also relates to methods of treating and/or preventing certain diseases and conditions by administering such a composition contained in such an aerosol can.
Discussion of the Background
Glycopyrronium bromide (also known as glycopyrrolate) is a muscarinic M3 anticholinergic agent used to reduce salivation associated with administration of certain anaesthetics, and as adjunctive therapy for peptic ulcers. It has also been reported to be effective in the treatment of asthmatic symptoms (Hansel et al., Chest 2005; 128:1974-1979, which is incorporated herein by reference in its entirety).
WO 2005/107873, which is incorporated herein by reference in its entirety, relates to the use of glycopyrrolate for the treatment of childhood asthma.
WO 01/76575, which is incorporated herein by reference in its entirety, discloses a controlled release formulation for pulmonary delivery of glycopyrrolate. The formulation is intended for use in the treatment of respiratory diseases, in particular of chronic obstructive pulmonary disease (COPD). The patent application focuses, essentially, on dry powder formulations suitable for delivery by means of a dry powder inhaler (DPI).
WO 2005/074918, which is incorporated herein by reference in its entirety, discloses combinations of glycopyrrolate with glucocorticoid drugs and their use for treating diseases of the respiratory tract.
WO 2005/110402, which is incorporated herein by reference in its entirety, discloses combinations of glycopyrrolate with a beta-2 agonist of the class of indane or of benzothiazole-2-one derivatives for the treatment of inflammatory or of obstructive airway diseases.
WO 2006/105401, which is incorporated herein by reference in its entirety, discloses combinations of an anticholinergic, a corticosteroid and a long-acting beta-2 agonist for the prevention and treatment of respiratory, inflammatory or obstructive airway diseases; glycopyrrolate is among the optional anticholinergic agents.
According to WO 2007/057223 and WO 2007/057222, both of which are incorporated herein by reference in their entireties, combinations of glycopyrronium bromide with an anti-inflammatory steroid, particularly mometasone furoate, are reported to provide a therapeutic benefit in the treatment of inflammatory and obstructive airways diseases.
WO 2007/057221 and WO 2007/057219, both of which are incorporated herein by reference in their entireties, respectively, relate to combinations of a glycopyrronium salt with an indanyl derivative beta-2 agonist (or analogue) or with an anti-inflammatory steroid, particularly mometasone furoate.
WO 00/07567, which is incorporated herein by reference in its entirety, discloses, in Example 4, a suspension aerosol formulation wherein to a mixture of micronized actives, namely formoterol fumarate, glycopyrronium bromide and disodium cromoglycate, a propellant mixture of HFA and dinitrogen monoxide, together with 2% by weight of ethanol, are added.
The “Martindale. The complete drug reference,” January 2002, monograph on glycopyrronium bromide (page 467), which is incorporated herein by reference in its entirety, shows that in investigations on compatibility of this substance with aqueous infusion solutions for injections and additives, the stability of glycopyrronium bromide is questionable above a pH 6, owing to ester hydrolysis.
US 2002/025299, which is incorporated herein by reference in its entirety, discloses pressurized aerosol solution formulations of different active ingredients among which is formoterol or its combinations with beclometasone dipropionate, further acidified by HCl and stored in given cans such as stainless steel or anodized aluminium, or even lined with an inert organic coating.
WO 2005/074900, which is incorporated herein by reference in its entirety, discloses an inhalable combination of an anticholinergic agent with a beta-2 mimetic agent for the treatment of inflammatory or obstructive respiratory diseases and, in the examples shows formulations of the R,R-enantiomer of glycopyrronium bromide in combination with formoterol, either as DPI formulation or pMDI suspension.
US 2006/0257324, which is incorporated herein by reference in its entirety, discloses the delivery of a combination of two or more dissolved drugs in a HFA propellant-cosolvent system, substantially having the same particle size distribution and thus allowing for their co-deposition in the same lung region tract. These formulations comprise a beta-2 agonist (formoterol or carmoterol being exemplified) and a corticosteroid (beclometasone dipropionate being exemplified), or an anticholinegic agent such as ipratropium, oxitropium, tiotropium or glycopyrronium bromide, these latter being only generically cited in the description.
Formoterol is a beta-2 adrenergic agonist drug capable of relaxing smooth muscle in the bronchi and opening the airways to reduce wheezing conditions. It is commonly used in the management of asthma and other respiratory conditions.
Recently, an effective combination therapy comprising formoterol fumarate and beclometasone dipropionate (BDP) has become available under the trade-name Foster®. Said product is designed to be delivered to the lungs through a variety of aerosol means also including pressurized metered dose inhalers (pMDI).
In this respect, it is known that aerosol solutions of formoterol fumarate are relatively unstable and have a short shelf-life when stored under suboptimal conditions. To obviate to this drawback, the Foster® composition has been properly developed by incorporating a suitable amount of inorganic acid in order to stabilize the formoterol component at a selected apparent pH range, for instance as described in EP 1 157 689, which is incorporated herein by reference in its entirety.
In WO 2011/076843, which is incorporated herein by reference in its entirety, it is disclosed that pMDI aerosol solution formulations comprising glycopyrronium bromide in combination with formoterol or salts thereof, optionally including an inhalation corticosteroid such as BDP, wherein a suitable amount of a mineral acid was added, in particular 1M HCl in the range of 0.1-0.3 μg/μl, so that both formoterol and glycopyrronium bromide components were properly stabilized. In addition, the above compositions enabled maintaining the amount of a degradation product, therein referred to as DP3, to low levels.
However, when using relatively high amounts of acid as a stabilizing adjuvant to both formoterol and glycopyrronium components, the amount of DP3 being detected upon storage for 3 months at 25° C. and 60% of relative humidity (RH), were indeed remarkable.
Therefore, as disclosed in WO 2011/076843, which is incorporated herein by reference in its entirety, a further step comprising removal of oxygen from the aerosol canister headspace, for instance by incorporating an oxygen purging step through vacuum crimping in the process of filling the aerosol canister, may be thus required so as to lower DP3 content.
During the formulation development of such combinations, the degradation product DP3 was then identified as being N-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide (see analytical details in the experimental section).
As the formation of this degradation product, when it is quantified significantly above the identification/qualification threshold (≥1.0% w/w with respect to the theoretical formoterol fumarate content of 6 μg/actuation [as defined in ICH Guideline Q3B(R2)]) may represent a potential issue for these pMDI combination formulations, means for lowering the DP3 content below an acceptable threshold, other than those known, involving oxygen removal and requiring a dedicated purging step in the filling of the aerosol canister during manufacturing, could be particularly advantageous.
As such, it would be thus desirable to provide a clinically useful aerosol combination product that combines the therapeutic benefits of formoterol or salts thereof or a solvate of said salt and glycopyrronium bromide, optionally in conjunction with additional active ingredients such as inhalation corticosteroid, in particular beclometasone dipropionate or budesonide, so that each individual pharmaceutically active component is properly delivered to the lungs in effective and consistent doses over an extended product lifetime, and ideally without the need for particular storage conditions of temperature or humidity, that could be otherwise required to maintain low levels of degradation products such as DP3.